Objective: In this study, we examined neuroprotective effects of rotigotine and involvement of serotonin 1A (5-HT1A) receptors on astrocytes in neuroprotective action of the drug using primary cultured cells and parkinsonian mice.

Background: We previously reported that stimulation of 5-HT1A receptors on astrocytes promoted astrocyte proliferation and upregulated an antioxidative molecule metallothionein (MT) to act as a neuroprotectant in parkinsonian mice. Rotigotine, a dopamine receptor agonist, also possesses a 5-HT1A agonistic property.

Methods: Primary cultured neurons and astrocytes were prepared from the mesencephalon and striata of Sprague-Dawley rat embryos at 15 days of gestation. Cultured astrocytes were treated with rotigotine (1 µM) and/or a 5-HT1A antagonist WAY100635 (10 nM) for 6 h or 24 h to evaluate nuclear translocation of Nrf2 or MT expression respectively. Mesencephalic neurons were treated with conditioned media from rotigotine- and/or WAY100635-treated astrocytes for 24 h followed by 6-hydroxydopamine (6-OHDA). Changes in the number of dopaminergic neurons were examined. The hemi-parkinsonian mice unilaterally lesioned by intrastriatal injections of 6-OHDA were treated with rotigotine (0.125, 0.25 or 0.5 mg/kg, s.c.) for 7 days, and immunohistochemical analyses were performed using brain slices.

Results: Rotigotine treatment induced nuclear translocation of Nrf2 and upregulated MT in astrocytes. Pretreatment with conditioned media from rotigotine-treated astrocytes significantly decreased 6-OHDA-induced dopaminergic neurotoxicity. These effects were completely blocked by 5-HT1A antagonist.

Conclusions: These results suggest that rotigotine exerts neuroprotective effects against dopaminergic neurodegeneration by targeting 5-HT1A receptors on astrocytes.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/rotigotine-protects-dopaminergic-neurons-by-targeting-serotonin-1a-receptors-on-astrocytes/